The Role of RAGE-Specific Inhibitors in Impairing Triple-negative breast cancer (TNBC) Progression and Metastasis

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Breast cancer is a complex and heterogeneous disease that poses significant challenges in terms of treatment and management.

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression.

Patients with TNBC have limited treatment options, and the development of targeted therapies is of utmost importance.

The receptor for advanced glycation end products (RAGE) is a cell surface receptor that plays a crucial role in various pathological conditions, including diabetes, cardiovascular disease, Alzheimer’s disease, and cancer progression and metastasis. RAGE is an attractive therapeutic target due to its heightened activity in pathological states and the availability of both biologic and small molecule inhibitors.

Among the small molecule inhibitors, TTP488 (Azeliragon) and FPS-ZM1 have shown promise in preclinical models of Alzheimer’s disease. In this study, the researchers aimed to investigate the efficacy of TTP488 compared to FPS-ZM1 in impairing TNBC progression and metastasis. Furthermore, they explored the underlying mechanisms through which RAGE mediates breast cancer progression and metastasis.

Methods and Results: The researchers utilized multiple in vivo models, including an orthotopic xenograft TNBC model (4175/NSG) and a tail vein injection model (4T1/BALBc), to evaluate the effects of RAGE inhibitors on metastasis. They found that both TTP488 and FPS-ZM1 significantly reduced metastasis in these models, with TTP488 exhibiting a more potent inhibitory effect than FPS-ZM1 at the same treatment dose. Interestingly, the impact of RAGE inhibition on primary tumor growth was more moderate and comparable between the two inhibitors.

To gain insights into the molecular mechanisms underlying these effects, the researchers performed transcriptomic analysis of tumor and metastatic tissue. They observed that both RAGE inhibitors affected overlapping gene signatures and pathways involved in cellular metabolism, cell cycle, cell adhesion, and apoptosis. Additionally, they found that RAGE inhibition impacted similar yet distinct biological processes in primary tumor cells compared to disseminated tumor cells at the transcript level, suggesting the presence of different biology required for tumor adaptation to metastatic sites.

In vitro experiments demonstrated that inhibition of RAGE with either TTP488 or FPS-ZM1 impaired metastatic driver mechanisms, including cell adhesion, migration, and invasion. Furthermore, protein array analysis of tumor intrinsic secreted factors in the serum revealed that RAGE inhibition downregulated proteins fundamental for driving metastatic processes, such as angiogenesis, epithelial-mesenchymal transition (EMT), inflammation, and oxidative stress.

The researchers also conducted phospho-proteomic analysis of tumors from the in vivo models, which revealed that RAGE inhibition affected critical signaling mechanisms involved in tumor progression and metastasis. Pathways such as STAT proteins, Akt, p53, p70 S6 kinase, RSK 1/2, and Pyk2 were found to be altered by RAGE inhibition, providing insights into the signaling pathways regulated by RAGE in breast cancer.

Discussion: The findings of this study demonstrate that TTP488, a RAGE-specific inhibitor, has a potent anti-metastatic effect in TNBC. The results indicate that RAGE plays a more significant role in breast cancer metastasis than primary tumor growth. The transcriptomic and proteomic analyses provide a comprehensive understanding of the gene signatures, pathways, and molecular mechanisms affected by RAGE inhibition. The study highlights the impact of RAGE on critical processes involved in metastasis, including cell adhesion, migration, invasion, angiogenesis, and EMT.

The limitations of the study include the focus on tumor intrinsic mechanisms and the lack of analysis on the role of RAGE in non-tumor cells and the tumor microenvironment. RAGE signaling has been shown to modulate host mechanisms and recruit proinflammatory and immunosuppressive myeloid immune cells. Future studies should investigate the contribution of non-tumor cells and the tumor microenvironment in RAGE-mediated metastasis.

Conclusion: In conclusion, this study provides compelling evidence for the efficacy of the RAGE-specific inhibitor TTP488 in impairing TNBC progression and metastasis. The research sheds light on the molecular mechanisms through which RAGE mediates breast cancer metastasis, including its impact on cell adhesion, migration, invasion, and various signaling pathways.

These findings support the potential clinical translation of TTP488 as a targeted therapy for metastatic breast cancer and other RAGE-driven pathological conditions. Further investigations are warranted to fully elucidate the role of RAGE in the tumor microenvironment and explore the therapeutic potential of RAGE inhibition in combination with existing treatment modalities.


reference link: https://www.nature.com/articles/s41523-023-00564-9

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